tbuckley/cabot-search huggingface dataset:
Slowing the Slide Down the Slippery Slope of Medical Assistance in Dying: Mutual Learnings for Canada and the US
Authors: Daryl Pullman
Journal: The American Journal of Bioethics (2023)

Canada and California each introduced legislation to permit medical assistance in dying in June, 2016. Each jurisdiction publishes annual reports on the number of deaths that occurred under their respective legislations in the previous years. The numbers are disturbingly different. In 2021, 486 individuals died under California's End of Life Option. In the same year 10,064 Canadians died under that country's Medical Assistance in Dying (MAiD) legislation. California has a slightly larger population than Canada, and while medically assisted deaths as a percentage of total deaths remained virtually unchanged in California from 2020-2021, Canada saw a 30% increase from 2020 to 2021. This essay examines some of the factors propelling Canada down the slippery slope of medically assisted suicide, as well as those that may be keeping California and other US jurisdictions from taking the slide. At a time of increasing pressure in many jurisdictions (both nationally and internationally) to liberalize access to medical assistance in dying, some lessons from this comparative analysis are offered.
Expanding on the Solutions to Reduce Neonatal Intensive Care Unit Morbidity and Mortality for Extremely Premature Infants—Looking Out the Hospital Window and Into the Neighborhoods
Authors: Christina M. Jäderholm, Lynne C. Messer
Journal: JAMA Network Open (2023)

Brynne A. Sullivan, MD; Ayush Doshi, BA; Pavel Chernyavskiy, PhD; Ameena Husain, DO; Alexandra Binai, BA; Rakesh Sahni, MBBS; Karen D. Fairchild, MD; J. Randall Moorman, MD; Colm P. Travers, MD; Zachary A. Vesoulis, MD
Endoscopic treatment for a hematoma-mediated colon obstruction caused by acupuncture: A rare case report
Authors: Shiwei Li, Siyu Sun, Guoxin Wang
Journal: Endoscopy (2023)

Corrected by: Correction: Endoscopic treatment for a hematoma-mediated colon obstruction caused by acupuncture: A rare case reportEndoscopy 2023; 55(S 01): C3-C3DOI: 10.1055/a-2092-1486
Endothelial mechanobiology in atherosclerosis
Authors: Xiaoli Wang, Yang Shen, Min Shang, Xiaoheng Liu, Lance L Munn
Journal: Cardiovascular Research (2023)

Abstract Cardiovascular disease (CVD) is a serious health challenge, causing more deaths worldwide than cancer. The vascular endothelium, which forms the inner lining of blood vessels, plays a central role in maintaining vascular integrity and homeostasis and is in direct contact with the blood flow. Research over the past century has shown that mechanical perturbations of the vascular wall contribute to the formation and progression of atherosclerosis. While the straight part of the artery is exposed to sustained laminar flow and physiological high shear stress, flow near branch points or in curved vessels can exhibit ‘disturbed’ flow. Clinical studies as well as carefully controlled in vitro analyses have confirmed that these regions of disturbed flow, which can include low shear stress, recirculation, oscillation, or lateral flow, are preferential sites of atherosclerotic lesion formation. Because of their critical role in blood flow homeostasis, vascular endothelial cells (ECs) have mechanosensory mechanisms that allow them to react rapidly to changes in mechanical forces, and to execute context-specific adaptive responses to modulate EC functions. This review summarizes the current understanding of endothelial mechanobiology, which can guide the identification of new therapeutic targets to slow or reverse the progression of atherosclerosis.
PP2A modulation overcomes multidrug resistance in chronic lymphocytic leukemia via mPTP-dependent apoptosis
Authors: Kallesh D. Jayappa, Brian Tran, Vicki L. Gordon, Christopher Morris, Shekhar Saha, Caroline C. Farrington, Caitlin M. O’Connor, Kaitlin P. Zawacki, Krista M. Isaac, Mark Kester, Timothy P. Bender, Michael E. Williams, Craig A. Portell, Michael J. Weber, Goutham Narla
Journal: Journal of Clinical Investigation (2023)

Targeted therapies such as venetoclax (Bcl-2 inhibitor) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). We previously reported that persister CLL cells in treated patients overexpress multiple anti-apoptotic proteins and display resistance to pro-apoptotic agents. Here, we demonstrated that multidrug resistant CLL cells in vivo exhibit apoptosis restriction at a premitochondrial level due to insufficient activation of the Bax and Bak proteins. Co-immunoprecipitation analyses with selective BH-domain antagonists revealed that the pleotropic pro-apoptotic protein (Bim) is prevented from activating Bax/Bak by "switching" interactions to other upregulated anti-apoptotic proteins (Mcl-1/Bcl-xL/Bcl-2). Hence, treatments that bypass Bax/Bak restriction are required to deplete these resistant cells in patients. Protein Phosphatase 2A (PP2A) contributes to oncogenesis and treatment resistance. We observed that a small molecule activator of PP2A (SMAP) induced cytotoxicity in multiple cancer cell lines and CLL samples, including multidrug resistant leukemia/lymphoma cells. The SMAP (DT-061) activated apoptosis in multidrug resistant CLL cells through induction of mitochondrial permeability transition pores (mPTP), independent of Bax/Bak. DT-061 inhibited the growth of wild type and Bax/Bak double knockout multidrug resistant CLL cells in a xenograft mouse model. Collectively, we discovered multidrug resistant CLL cells in patients, and validated a pharmacologically tractable pathway to deplete this reservoir.
(Nano)platforms in breast cancer therapy: Drug/gene delivery, advanced nanocarriers and immunotherapy
Authors: Milad Ashrafizadeh, Ali Zarrabi, Ashkan Bigham, Afshin Taheriazam, Yalda Saghari, Sepideh Mirzaei, Mehrdad Hashemi, Kiavash Hushmandi, Hassan Karimi‐Maleh, Ehsan Nazarzadeh Zare, Esmaeel Sharifi, Yavuz Nuri Ertas, Navid Rabiee, Gautam Sethi, Mingzhi Shen
Journal: Medicinal Research Reviews (2023)

Abstract Breast cancer is the most malignant tumor in women, and there is no absolute cure for it. Although treatment modalities including surgery, chemotherapy, and radiotherapy are utilized for breast cancer, it is still a life‐threatening disease for humans. Nanomedicine has provided a new opportunity in breast cancer treatment, which is the focus of the current study. The nanocarriers deliver chemotherapeutic agents and natural products, both of which increase cytotoxicity against breast tumor cells and prevent the development of drug resistance. The efficacy of gene therapy is boosted by nanoparticles and the delivery of CRISPR/Cas9, Noncoding RNAs, and RNAi, promoting their potential for gene expression regulation. The drug and gene codelivery by nanoparticles can exert a synergistic impact on breast tumors and enhance cellular uptake via endocytosis. Nanostructures are able to induce photothermal and photodynamic therapy for breast tumor ablation via cell death induction. The nanoparticles can provide tumor microenvironment remodeling and repolarization of macrophages for antitumor immunity. The stimuli‐responsive nanocarriers, including pH‐, redox‐, and light‐sensitive, can mediate targeted suppression of breast tumors. Besides, nanoparticles can provide a diagnosis of breast cancer and detect biomarkers. Various kinds of nanoparticles have been employed for breast cancer therapy, including carbon‐, lipid‐, polymeric‐ and metal‐based nanostructures, which are different in terms of biocompatibility and delivery efficiency.
Implementation of self‐binding directives: recommendations based on expert consensus and input by stakeholders in three European countries
Authors: Matthé Scholten, Simone Agnes Efkemann, Mirjam Faissner, Marleen Finke, Jakov Gather, Tania Gergel, Astrid Gieselmann, Lia van der Ham, Georg Juckel, Laura van Melle, Gareth Owen, Sarah Potthoff, Lucy A. Stephenson, George Szmukler, Astrid Vellinga, Jochen Vollmann, Yolande Voskes, Anna Werning, Guy Widdershoven
Journal: World Psychiatry (2023)

participate and thrive at work.
Adjuvant Treatments for Surgically Resected Non–Small Cell Lung Cancer Harboring <i>EGFR</i> Mutations
Authors: Antonio Passaro, Tony S. K. Mok, Ilaria Attili, Yi-Long Wu, Masahiro Tsuboi, Filippo de Marinis, Solange Peters
Journal: JAMA Oncology (2023)

The use of adjuvant chemotherapy for stage IB-IIIA resected non-small cell lung cancer (NSCLC) has limited benefit for improving cure rates. The proportion of epidermal growth factor receptor (EGFR) alterations among patients with resected NSCLC is comparable to that observed in patients with advanced disease, and the use of EGFR tyrosine kinase inhibitors (TKIs) has been demonstrated to prolong disease-free survival (DFS). With recent approval of osimertinib in this context, a focus on the rapidly evolving scenario and future perspective in clinical practice is needed and was the aim of the current review.Randomized phase 3 clinical trials demonstrated DFS benefit with adjuvant EGFR TKI therapy in patients with resected EGFR mutation-positive NSCLC. The most recent trial (ADAURA) assessed 3-year adjuvant osimertinib and showed consistent DFS benefit and a significant role of the intervention in preventing the occurrence of brain metastasis. However, the role of adjuvant chemotherapy, the appropriate duration of treatment, the management of disease relapse, and the effective cure rate remain undetermined. A deeper investigation on molecular biomarkers, covariant patterns, and dynamic monitoring of postsurgical circulating DNA would be helpful for the implementation of future strategies to further improve survival rates after adjuvant therapy for EGFR mutation-positive NSCLC.Adjuvant osimertinib revolutionized the treatment algorithm for patients with stage IB-IIIA resected EGFR mutation-positive NSCLC. Further evidence driven by clinical issues will be key for further optimization of the goals of adjuvant treatment in these patients.
Association of Weight Loss in Ambulatory Care Settings With First Diagnosis of Lung Cancer in the US
Authors: Larry G. Kessler, Brian D. Nicholson, Hannah A. Burkhardt, Jason Oke, Matthew J. Thompson
Journal: JAMA Network Open (2023)

Importance Lung cancer, the US’s leading cause of cancer death, is often diagnosed following presentation to health care settings with symptoms, and many patients present with late-stage disease. Objective To investigate the association between weight loss and subsequent diagnosis of incident lung cancer in an ambulatory care population and to assess whether recorded weight change had higher odds of lung cancer diagnosis than objective measurements. Design, Setting, and Participants This case-control study included patients visiting a US academic medical center between January 1, 2012, and December 31, 2019. Data were derived from US ambulatory care electronic health records from the University of Washington Medical Center linked to the local Surveillance, Epidemiology, and End Results cancer registry. Cases were identified from patients who had a primary lung cancer diagnosis between 2012 and 2019; controls were matched on age, sex, smoking status, and presenting to the same type of ambulatory clinic as cases. Data were analyzed from March 2022 through January 2023. Exposure Continuous and categorical weight change were assessed. Main Outcomes and Measures Odds ratios estimating the likelihood of a diagnosis of lung cancer were calculated using univariable and multivariable conditional logistic regression. Results A total of 625 patients aged 40 years or older with a first primary lung cancer diagnosis and 4606 matched controls were included (1915 [36.6%] ages 60 to 69 years; 418 [8.0%] Asian, 389 [7.4%] Black, 4092 [78.2%] White). In unadjusted analyses, participants with weight loss of 1% to 3% (odds ratio [OR], 1.12; 95% CI, 0.88-1.41), 3% to 5% (OR, 1.36; 95% CI, 0.99-1.88), or 5% to 10% (OR, 1.23; 95% CI, 0.82-1.85) over a 2-year period did not have statistically significantly increased risk of lung cancer diagnosis compared with those who maintained a steady weight. However, participants with weight loss of 10% to 50% had more than twice the odds of a lung cancer diagnosis (OR, 2.27; 95% CI, 1.27-4.05). Most categories of weight loss showed significant associations with an increased risk of lung cancer diagnosis for at least 6 months prior to diagnosis. Patients who had weight loss both recorded in clinicians’ notes and measured had higher odds of lung cancer compared with patients who had only recorded (OR, 1.26; odds; 95% CI, 1.04-1.52) or measured (OR, 8.53; 95% CI, 6.99-10.40) weight loss. Conclusions and Relevance In this case-control study, weight loss in the prior 6 months was associated with incident lung cancer diagnosis and was present whether weight loss was recorded as a symptom by the clinician or based on changes in routinely measured weight, demonstrating a potential opportunity for early diagnosis. The association between measured and recorded weight loss by clinicians presents novel results for the US.
Successful retrieval of a fractured biliary guidewire using a newly developed endoscopic tapered sheath
Authors: Yuki Mori, Akira Kurita
Journal: Endoscopy (2023)

An 81-year-old man with Bismuth–Corlette type II perihilar cholangiocarcinoma ([Fig. 1]) underwent endoscopic retrograde cholangiopancreatography (ERCP). Cholangiography showed a hilar stricture that was so severe that the biopsy forceps could not be passed alongside the tumor ([Fig. 2 a]). During this ERCP, a guidewire was fractured. An endoscopic nasobiliary drainage tube was inserted into the right anterior duct, without removal of the fragment being attempted ([Fig. 2 b]).
Nomenclature, diagnosis and management of drug-induced autoimmune-like hepatitis (DI-ALH): An expert opinion meeting report
Authors: Raúl J. Andrade, Guruprasad P. Aithal, Ynto S. de Boer, Rodrigo Liberal, Alexander Gerbes, Arie Regev, Benedetta Terziroli Beretta-Piccoli, Christoph Schramm, David E. Kleiner, Eleonora De Martin, Gerd A. Kullak-Ublick, Guido Stirnimann, Harshad Devarbhavi, John M. Vierling, Michael P. Manns, Marcial Sebode, Maria Carlota Londoño, Mark Avigan, Mercedes Robles-Diaz, Miren García-Cortes, Edmond Atallah, Michael Heneghan, Naga Chalasani, Palak J. Trivedi, Paul H. Hayashi, Richard Taubert, Robert J. Fontana, Sabine Weber, Ye Htun Oo, Yoh Zen, Anna Licata, M Isabel Lucena, Giorgina Mieli-Vergani, Diego Vergani, Einar S. Björnsson
Journal: Journal of Hepatology (2023)

Drug-induced liver injury (DILI) can mimic almost all other liver disorders. A phenotype increasingly ascribed to drugs is autoimmune-like hepatitis (ALH). This article summarises the major topics discussed at a joint International Conference held between the Drug-Induced Liver Injury consortium and the International Autoimmune Hepatitis Group. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH). Previous studies have revealed that patients with DI-ALH and those with idiopathic AIH have very similar clinical, biochemical, immunological and histological features. Differentiating DI-ALH from AIH is important as patients with DI-ALH rarely require long-term immunosuppression and the condition often resolves spontaneously after withdrawal of the implicated drug, whereas patients with AIH mostly require long-term immunosuppression. Therefore, revision of the diagnosis on long-term follow-up may be necessary in some cases. More than 40 different drugs including nitrofurantoin, methyldopa, hydralazine, minocycline, infliximab, herbal and dietary supplements (such as Khat and Tinospora cordifolia) have been implicated in DI-ALH. Understanding of DI-ALH is limited by the lack of specific markers of the disease that could allow for a precise diagnosis, while there is similarly no single feature which is diagnostic of AIH. We propose a management algorithm for patients with liver injury and an autoimmune phenotype. There is an urgent need to prospectively evaluate patients with DI-ALH systematically to enable definitive characterisation of this condition.
Genetic immune escape landscape in primary and metastatic cancer
Authors: Francisco Martínez-Jiménez, Peter Priestley, Charles Shale, Jonathan Baber, Erik Rozemuller, Edwin Cuppen
Journal: Nature Genetics (2023)

Studies have characterized the immune escape landscape across primary tumors. However, whether late-stage metastatic tumors present differences in genetic immune escape (GIE) prevalence and dynamics remains unclear. We performed a pan-cancer characterization of GIE prevalence across six immune escape pathways in 6,319 uniformly processed tumor samples. To address the complexity of the HLA-I locus in the germline and in tumors, we developed LILAC, an open-source integrative framework. One in four tumors harbors GIE alterations, with high mechanistic and frequency variability across cancer types. GIE prevalence is generally consistent between primary and metastatic tumors. We reveal that GIE alterations are selected for in tumor evolution and focal loss of heterozygosity of HLA-I tends to eliminate the HLA allele, presenting the largest neoepitope repertoire. Finally, high mutational burden tumors showed a tendency toward focal loss of heterozygosity of HLA-I as the immune evasion mechanism, whereas, in hypermutated tumors, other immune evasion strategies prevail.
Exposure–response relationships for personal exposure to fine particulate matter (PM2·5), carbon monoxide, and black carbon and birthweight: an observational analysis of the multicountry Household Air Pollution Intervention Network (HAPIN) trial
Authors: Kalpana Balakrishnan, Kyle Steenland, Thomas Clasen, Howard Chang, Michael Johnson, Ajay Pillarisetti, Wenlu Ye, Luke P Naeher, Anaite Diaz-Artiga, John P McCracken, Lisa M Thompson, Ghislaine Rosa, Miles A Kirby, Gurusamy Thangavel, Sankar Sambandam, Krishnendu Mukhopadhyay, Naveen Puttaswamy, Vigneswari Aravindalochanan, Sarada Garg, Florien Ndagijimana, Stella Hartinger, Lindsay J Underhill, Katherine A Kearns, Devan Campbell, Jacob Kremer, Lance Waller, Shirin Jabbarzadeh, Jiantong Wang, Yunyun Chen, Joshua Rosenthal, Ashlinn Quinn, Aris T Papageorghiou, Usha Ramakrishnan, Penelope P Howards, William Checkley, Jennifer L Peel
Journal: The Lancet Planetary Health (2023)

Household air pollution (HAP) from solid fuel use is associated with adverse birth outcomes, but data for exposure-response relationships are scarce. We examined associations between HAP exposures and birthweight in rural Guatemala, India, Peru, and Rwanda during the Household Air Pollution Intervention Network (HAPIN) trial.
Autologous mesenchymal stem cells offer a new paradigm for salivary gland regeneration
Authors: Milos Marinkovic, Olivia N Tran, Hanzhou Wang, Parveez Abdul-Azees, David D Dean, Xiao-Dong Chen, Chih-Ko Yeh
Journal: International Journal of Oral Science (2023)

Salivary gland (SG) dysfunction, due to radiotherapy, disease, or aging, is a clinical manifestation that has the potential to cause severe oral and/or systemic diseases and compromise quality of life. Currently, the standard-of-care for this condition remains palliative. A variety of approaches have been employed to restore saliva production, but they have largely failed due to damage to both secretory cells and the extracellular matrix (niche). Transplantation of allogeneic cells from healthy donors has been suggested as a potential solution, but no definitive population of SG stem cells, capable of regenerating the gland, has been identified. Alternatively, mesenchymal stem cells (MSCs) are abundant, well characterized, and during SG development/homeostasis engage in signaling crosstalk with the SG epithelium. Further, the trans-differentiation potential of these cells and their ability to regenerate SG tissues have been demonstrated. However, recent findings suggest that the "immuno-privileged" status of allogeneic adult MSCs may not reflect their status post-transplantation. In contrast, autologous MSCs can be recovered from healthy tissues and do not present a challenge to the recipient's immune system. With recent advances in our ability to expand MSCs in vitro on tissue-specific matrices, autologous MSCs may offer a new therapeutic paradigm for restoration of SG function.
Survival Outcomes in Patients With Hormone Receptor–Positive Metastatic Breast Cancer With Low or No <i>ERBB2</i> Expression Treated With Targeted Therapies Plus Endocrine Therapy
Authors: Jason A. Mouabbi, Akshara Singareeka Raghavendra, Roland L. Bassett, Amy Hassan, Debasish Tripathy, Rachel M. Layman
Journal: JAMA Network Open (2023)

Importance Approximately 45% to 60% of hormone receptor (HR)–positive metastatic breast cancer (mBC) shows a low-level expression of ERBB2 . Low ERBB2 expression is defined as ERBB2 immunohistochemical expression of 1+ or 2+ with a negative ERBB2 amplification by in situ hybridization. The efficacy of the antibody-drug conjugate trastuzumab deruxtecan in low- ERBB2 , HR-positive mBC has been practice changing. However, there are conflicting data on the prognostic value of low ERBB2 expression in HR-positive mBC and whether low ERBB2 expression is a separate entity. Objective To examine whether outcomes differ by immunohistochemical analysis for patients with HR-positive mBC with low ERBB2 expression vs those without ERBB2 expression when treated with targeted therapy (TT) plus endocrine therapy (ET). Design, Setting, and Participants This single-institution cohort study used prospectively collected electronic data from the MD Anderson Cancer Center for patients with a diagnosis of HR-positive mBC treated with ET in combination with a TT (cyclin-dependent kinase 4/6 inhibitors [CDK4/6is], everolimus, or alpelisib) between January 1, 2010, and December 31, 2021. Exposure HR-positive mBC with either low or no ERBB2 expression. Main Outcome and Measures The main outcomes were median progression-free survival and overall survival. Data on demographic characteristics, estrogen and progesterone receptor status, ERBB2 status, histologic subtype, menopausal status, treatment duration, and survival status were collected. Results A total of 1585 women (median [range] age, 51 [24-92] years) were included in the study. Of these women, 1013 (63.9%) had mBC with low ERBB2 expression and 572 (36.1%) had mBC with no ERBB2 expression. A total of 1084 (68.4%) were treated with a CDK4/6i (912 patients were treated in the first line and 172 were treated in the second line); 475 (30.0%) received everolimus and 26 (1.6%) received alpelisib. In the patients who received a first-line CDK4/6i, 618 (67.8%) received an aromatase inhibitor as their ET backbone and 265 (29.1%) received fulvestrant. With a median follow-up time of 17.9 months (range, 1-111 months), progression-free survival and overall survival were not statistically different between the patients with low and no ERBB2 expression treated with TT plus ET. Conclusions and Relevance In this cohort study of patients with HR-positive mBC treated with TT plus ET, low ERBB2 expression did not have a significant association with prognosis.